Long-term follow-up of relapsed childhood acute lymphoblastic leukaemia

We have reviewed the outcome after relapse in a cohort of 505 children with acute lymphoblastic leukaemia (ALL) seen at a single institution. The majority of relapses (74%) occurred within 3 years from diagnosis, and most involved the bone marrow alone or with overt extramedullary relapse. Early relapse was more common in children with T-ALL and those with unfavourable cytogenetics. Factors influencing second remission included length of first remission and type of relapse. Children who had not received previous cranial irradiation had a superior survival. The German relapse score involving length of first remission, site of relapse and immunophenotype was highly predictive of outcome: event-free survival with 95% confidence intervals at 6 years for patients who received modern treatment [intensive chemotherapy or bone marrow transplantation (BMT)] was 78% (51-92%) for standard risk, 41% (33-49%) for intermediate risk and 19% (10-31%) for highest risk. Retrospective comparison of BMT with chemotherapy showed no difference in the intermediate-risk group but a possible advantage in the highest risk group. Follow-up of 235 patients who relapsed after chemotherapy and received a third course of treatment showed an extremely high early attrition rate, but a small number of patients survived in third remission. We conclude that new approaches are needed to individualize therapy in intermediate-risk patients and to improve the outcome for those in the highest risk group. Only a small number of children can be treated effectively in third remission.     

Comparison of bone marrow transplant and chemotherapy for relapsed childhood acute lymphoblastic leukaemia: the MRC UKALL X experience

We examined the outcome of the 489 children with acute lymphoblastic leukaemia (ALL) who relapsed in the UKALL X trial, and produced graphical displays of adjusted comparisons of event-free survival (EFS) for chemotherapy versus bone marrow transplantation (BMT) from a sibling or volunteer unrelated donor, and autologous BMT (ABMT).
EFS at 5 years was only 3% (95% CI 0–6%) for children who relapsed in the bone marrow (BM) within 2 years of diagnosis, irrespective of type of post-relapse treatment, whereas for those with late extramedullary relapse it was 66% (95% CI 48–85%). Comparison of the types of treatment did not show benefit for ABMT. For allogeneic BMT the overall reduction in the odds of an event was 26% (95% CI 1–51%) (2 P  = 0.05), resulting in an absolute increase in 5-year event-free survival of 14% (from 26.4% to 40.7%).
New approaches are needed for children with early BM relapses whose prognosis is virtually hopeless with current therapy; however, a conventional chemotherapy approach may be justifiable for late extramedullary relapses. For the remaining patients (71%), with later BM or early extramedullary relapses, the optimal treatment is still not clear. This uncertainty warrants a formal randomized comparison of BMT and chemotherapy, to avoid the biases due to unmeasurable selection factors.     

Allogeneic bone marrow transplantation versus chemotherapy in high-risk childhood acute lymphoblastic leukaemia in first remission

We compared the outcome of children with high-risk acute lymphoblastic leukaemia (HR-ALL) in first complete remission (first CR) treated with chemotherapy (CHEMO) or with allogeneic bone marrow transplantation (BMT) in a multicentre study.   All children treated by the Italian Paediatric Haematology Oncology Association for HR-ALL in first CR between 1986 and 1994 were eligible for the study. 30 children were given BMT at a median of 4 months from first CR, with preparative regimens including total-body irradiation ( n  =25/30). 130 matched controls for BMT patients were identified among 397 HR-ALL CHEMO patients. Matching on main prognostic factors and duration of first CR was adopted to control the selection and time-to-transplant biases. The comparative analysis was based on the results of a stratified Cox model. The estimated hazard ratios of BMT versus CHEMO at 6 months, 1 year and 2 years after CR were 1.38 (CI 0.59–3.24), 0.69 (CI 0.27–1.77) and 0.35 (CI 0.06–1{\raise 5mu ..91), with an overall non-significant difference between the two groups ( P  = 0.34). With a median follow-up of 4 years, the disease-free survival was 58.5% (SE 9.3) in the BMT group and 47.7% (SE 4.8) in the CHEMO group, at 4 years from CR. Non-leukaemic death occurred in 4% of CHEMO and 10% of BMT patients. In the BMT group the estimated cumulative incidence of relapse at 1.5 years from CR was 31.5% (SE 8.8) and did not change thereafter, whereas in the CHEMO group the corresponding figure was 29.2% (SE 4.1) and the incidence continued to increase thereafter (48.2% (SE 4.8) at 4 years from CR).   The results of this study suggest that, with respect to the CHEMO group, the higher risk of early failure in the BMT group is outweighed by the lower risk of relapse after 1 year. Results prompt the need for a prospective study, in order to demonstrate the likely advantage of BMT in HR childhood ALL in first CR.     

Clonal stability in late-relapsing childhood lymphoblastic leukaemia

We report stability of a clonal immunoglobulin heavy chain (IgH) gene rearrangement in a case of childhood acute lymphoblastic leukaemia (ALL) relapsing 17 years after completion of first-line therapy. Clonal stability was shown by polymerase chain reaction amplification of the hypervariable CDRIII region of IgH gene. Identically sized products from the original diagnostic and the second presentation samples were obtained and direct sequencing confirmed complete sequence homology. Absence of clonal evolution together with recent reports of persistent minimal residual disease in patients in long-term complete remission, suggests that ‘cure’ of childhood ALL may be critically dependent on effective immune surveillance to keep such disease below clinically significant levels.     

Minimal residual disease prior to stem cell transplant for childhood acute lymphoblastic leukaemia

Allogeneic stem cell transplantation (SCT) is a highly effective therapy for childhood acute lymphoblastic leukaemia (ALL). Concerns about unnecessary toxicity and expense mean that SCT is currently largely reserved for children who cannot be cured with chemotherapy. Not surprisingly, many such children also fail SCT. Retrospective studies have shown that a single analysis of minimal residual disease (MRD) pre-SCT identified those at highest risk of relapse. It is now appropriate to call for the universal incorporation of standardized MRD testing into SCT protocols as the next step to maximize the clinical impact of this technology in ALL.     

New treatment strategies in childhood acute lymphoblastic leukaemia

Today, 80% of paediatric patients with acute lymphoblastic leukaemia (ALL) can be cured. To reduce the rate of relapses, but also to limit treatment morbidity, risk-adapted treatment has been attempted after identifying the most specific prognostic factors. In addition to clinical factors (e.g. age, WBC), the immunophenotype and cytogenetic results, the early in vivo treatment response as determined by cytology had evolved as the most important predictor for relapse. The lack of specificity of most prognostic factors stimulated the search for more relevant parameters. Detection of minimal residual disease (MRD) at defined time points by identifying clone-specific T-cell receptor- (TCR) or immunoglobulin (Ig) gene rearrangements can provide new, highly specific prognostic information which allows definition of new risk groups. The high sensitivity of the method is a prerequisite for applying treatment reduction in patients with fast clearance of leukaemia. Persistent disease is an indication for treatment modification and intensification. Logistics and quality control are demanding but are essential for the introduction of this new technology into clinical practice.     

Soluble l-selectin (sCD62L) in relapsed childhood acute lymphoblastic leukaemia

Soluble l-selectin (sCD62L) plasma concentrations at diagnosis and outcome were investigated in 193 children at first relapse of acute lymphoblastic leukaemia (ALL) after treatment according to the Berlin-Frankfurt-Münster relapsed ALL multicentre trials, ALL-REZ BFM 95 and 96. sCD62L was low (< fifth paediatric reference percentile) in 63 (33%) and high (> 95th percentile) in 36 (19%) children, and was independent of remission duration, sex, BCR-ABL fusion or extramedullary disease. High sCD62L was associated with circulating blasts and T-cell phenotype. More initial adverse events occurred in children with high and low levels of sCD62L (23 out of 99) than in those with normal levels (9 out of 94, P = 0.018). Among 75 worst-prognosis patients (risk groups S3/S4, isolated bone marrow relapse occurring less than 6 months after elective cessation of front-line therapy, or T-cell phenotype with bone marrow involvement), 27 had low sCD62L and decreased event-free survival (EFS) probability (PEFS5 = 0.09 at 5 years) and duration (219 d) compared with normal sCD62L (29 out of 75, PEFS5 = 0.24, 640 d, P = 0.01). Low (44 out of 118), normal (72 out of 118), and high (19 out of 118) sCD62L non-S3/S4 patients fared similarly (average PEFS5 = 0.45, 1369 d; P = 0.5). Low sCD62L may be a marker of malignant blasts replacing normal sCD62L-producing haematopoietic cells. In children with first relapse of ALL and worst prognosis, plasma sCD62L may be useful for risk-adapted stratification.     

Intraocular relapse of childhood acute lymphoblastic leukaemia

Relapse of childhood acute lymphoblastic leukaemia (ALL) involving the eye is a rare but challenging problem. Twenty cases occurred in patients treated on the Medical Research Council United Kingdom Acute Lymphoblastic Leukaemia XI and ALL97 trials between 1991 and 2001, representing 2.2% of ALL relapses. Seventeen occurred as a first relapse, either in isolation or combined with relapse at another site, and three occurred as a second relapse. All patients with intraocular disease at first relapse were treated with both chemotherapy and radiotherapy, but the doses and protocols used varied. Eleven of these 17 patients are alive and in complete remission with a median follow up of 4 years 2 months from relapse. All 11 children that were treated with a full chemotherapy relapse protocol, together with local radiotherapy have survived. Patients treated with chemotherapy of shorter duration and intensity, despite radiotherapy and/or bone marrow transplantation, did poorly with only one survivor, currently in chronic relapse. Consequently, we suggest that children with eye relapse of ALL be treated with an intensive relapse chemotherapy protocol with local ocular radiotherapy, whether the relapse occurs in isolation or in combination with relapse at another site.     

Relapse of acute lymphoblastic leukaemia 14 years after presentation: use of molecular techniques to confirm true re-emergence

SUMMARY. Late relapse after successful treatment of acute lymphoblastic leukaemia (ALL) in children is well recognized but rare. It is often uncertain whether this represents a true relapse of the original disease or a second malignancy. We present the case of a patient who relapsed 14 years after the original diagnosis of childhood ALL in whom both the orignal leukaemic cells and those taken at relapse had an identical T cell receptor gamma (TCRG) gene rearrangement. This analysis confirms that this relapse is a true re-emergence of the patient's original disease. The term 'cure' should be used with caution in childhood ALL, even after long periods in continuous remission.     

P-glycoprotein is an independent prognostic factor predicting relapse in childhood acute lymphoblastic leukaemia: results of a 6-year prospective study

P-glycoprotein (P-gp), a cellular drug-efflux pump, is thought to be one of the major causes of multidrug resistance (MDR) in malignancies. Since therapeutic strategies are being developed to circumvent drug resistance by inhibiting P-gp function, large prospective studies evaluating the clinical relevance of P-gp in childhood acute lymphoblastic leukaemia (ALL) are warranted. P-gp expression was evaluated over a period of 6 years in 102 consecutive patients with de novo childhood ALL and in 35 children with relapse of ALL. Bone marrow and blood smears were studied immunocytochemically with two monoclonal antibodies at initial diagnosis and at relapse. P-gp expression was found in 14 (14%) patients at initial diagnosis. After induction treatment, complete remission was achieved in 100/102 patients (98%), of whom 19 relapsed. Cumulative event-free survival was significantly higher in the P-gp-negative group compared with the P-gp-positive population (Logrank P = 0.02). Multivariate analysis showed the results to be independent of age, WBC count and karyotype, and concomitantly underlined the importance of MDR1 phenotype detection in childhood ALL. P-gp expression was more frequently found at relapse (34%) than at primary diagnosis (P = 0.01). In the relapsed patient group, P-gp-positive patients had a 2-fold greater risk for adverse clinical outcome than the P-gp-negative relapsed patients. P-gp expression was not induced by exposure to previous chemotherapy since the majority of P-gp-negative patients remained negative at relapse. P-glycoprotein expression in newly diagnosed childhood ALL is an independent adverse prognostic parameter with a predictive value for relapse.     

ALL R-87 protocol in the treatment of children with acute lymphoblastic leukaemia in early bone marrow relapse

Seventy-three children with acute lymphoblastic leukaemia (ALL) in first bone marrow (BM) relapse, occurring within 30 months from complete remission (CR), were enrolled in an Italian cooperative study (ALL R-87 protocol). This treatment programme consisted of an induction phase with intermediate-dose cytarabine (IDARA-C) plus idarubicin (IDA) and prednisone (PDN), followed by a multidrug consolidation therapy and bone marrow transplant (BMT). 55/73 children achieved CR (75.3%); 15 (20.5%) failed to respond and three (4.2%) died during induction. The response rate was significantly higher for children with a first CR duration 12 months (P = 0.0005) and for those with a white blood cell (WBC) count at relapse <20 × 10⁹/l (P=0.004). The estimated disease-free survival (DFS ± SE) at 82 months was 0.18 ± 0.05 for all responders, and 0.70 ± 0.14 for allotransplanted patients versus 0.05 ± 0.05 for those autografted (P = 0.001). The estimated probabilities of survival ± SE and event-free survival (EFS ± SE) at 83 months were 0.16 ± 0.07 and 0.13 ± 0.04, respectively, for all enrolled children. Univariate analysis showed that age <10 years at initial diagnosis and B-lineage immunophenotype favourably influenced both DFS (P = 0.001) and EFS probabilities (P = 0.0014 and P = 0.012, respectively), whereas a first CR duration 12 months and a WBC count at relapse <20 × 10⁹/l were associated only with a better EFS rate (P = 0.026 and P = 0.004, respectively). Our results show the efficacy of the IDA plus IDARA-C schedule used in the ALL R-87 protocol in high-risk relapsed ALL children. Allogeneic BMT proved effective for patients with an HLA sibling donor. In a multivariate analysis, age 10 years at initial diagnosis (P = 0.016) and WBC count at relapse 20 × 10⁹/l (P = 0.048) were independently associated with a worse disease outcome.     

Donor lymphocyte infusion for childhood acute lymphoblastic leukaemia relapsing after bone marrow transplantation

Four children with acute lymphoblastic leukaemia (ALL) who relapsed after allogeneic bone marrow transplantation (BMT) were treated with donor lymphocyte infusion (DLI) without prior conditioning. Three patients had previously received a non-T-cell-depleted matched sibling BMT and the fourth had a T-cell-depleted matched unrelated BMT. Two patients developed grade III–IV acute graft-versus-host-disease (GVHD) of the skin, which required intervention. Both are alive in complete haematological remission 7 and 10 months from DLI with chronic GVHD of the skin requiring immunosuppressive therapy. A third patient went into haematological remission 6 weeks after DLI, but with no clinical evidence of GVHD. His bone marrow remained in remission 11 months post-DLI despite the disease (ALL) relapsing in extramedullary sites. The fourth patient showed no clinical or haematological response to three consecutive doses of DLI given at 4-weekly intervals and died from progressive disease 11 months after relapse. These preliminary observations indicate that in constrast to experience in adult ALL, DLI may be effective in inducing sustained remission in children with ALL relapsing after BMT, and a response may occur even in the absence of clinical evidence of GVHD.     

Genome‐wide DNA methylation profiling predicts relapse in childhood B‐cell acute lymphoblastic leukaemia

Low‐dose decitabine has encouraging activity and tolerability in adults with acute myeloid leukaemia (AML), but paediatric experience is lacking. We report our retrospective experience with decitabine in eight children and young adults (median age 4 years) with refractory/relapsed AML, who had failed multiple regimens or were not candidates for standard retrieval regimens due to prior toxicities. Three of eight patients (38%) had complete response (CR; 1 each of CR, CR with incomplete platelet recovery and CR with incomplete count recovery). Best responses were observed after a median of 2·5 cycles (range 1–4 cycles). Four patients received subsequent allogeneic stem cell transplant, and two remain in long‐term CR.     

Beneficial and harmful effects of anthracyclines in the treatment of childhood acute lymphoblastic leukaemia: a systematic review and meta-analysis

Anthracyclines are used to treat childhood acute lymphoblastic leukaemia (ALL) but non-randomized studies suggest that cardiotoxicity may be a problem. Individual patient data from trials in childhood ALL that randomized anthracyclines or methods of reducing cardiotoxicity were analysed by standard meta-analysis methods. Results were grouped and combined according to: addition of an anthracycline to standard therapy, type of anthracycline, mode of administration, and the use of a cardioprotectant. Data from 958 patients in 4 trials, recruiting between 1972 and 1984, showed that addition of an anthracycline reduced bone marrow relapse and, non-significantly, non-bone marrow relapse, resulting in an increased relapse-free interval. However there was a non-significant increase in induction failures, and in deaths in first remission. Event-free survival at 5 years was 56·7% with anthracycline versus 52·8% without (Odds Ratio = 0·91; 95% Confidence Interval = 0·76–1·10; P  = 0·3). There were no significant differences found in other treatment comparisons. The limited data from trials did not demonstrate differences in clinically evident cardiotoxicity. Anthracyclines are effective against bone marrow relapse but have not been shown to significantly increase event free survival in childhood ALL. The evidence on type of anthracycline, method of administration or use of cardioprotectant was insufficient to be able to rule out important differences.     

PCR assessment of bone marrow status in 'isolated'extramedullary relapse of childhood B-precursor acute lymphoblastic leukaemia

SUMMARY. Approximately one-third of first relapses of childhood ALL occur at an extramedullary site without morphological evidence of bone marrow disease. However, the high incidence of subsequent medullary relapse in these cases strongly suggests that leukaemia is present at submicroscopic levels at the time of 'isolated'relapse. PCR analysis of immunoglobulin heavy chain (IgH) and T-cell receptor (TCR) gene rearrangements now allows detection of leukaemia at levels as low as 0.001%. We have therefore used this technique to reassess bone marrow status at morphologically isolated relapse in 13 children with B-lineage ALL (11 with off-treatment relapses, two on treatment). In 12 of these 13 patients marrow disease was detectable by PCR at the time of this relapse—in all cases at levels below the threshold of light microscopy. Where relapse occurred off-therapy this indicated re-emergence of disease, since MRD has never been detected by PCR at this stage in patients remaining in long-term remission. In both patients who relapsed on-therapy the level of MRD at the time of relapse represented an increase on that seen in their previous marrow sample. We conclude that re-emerging bone marrow disease can be detected in most cases of 'isolated'relapse when investigated by this highly sensitive technique. Our findings at a molecular level confirm a long-held clinical suspicion and indicate that full systemic re-induction as well as local therapy is obligatory for these children.     

Unrelated donor bone marrow transplantation for children with relapsed acute lymphoblastic leukaemia in second complete remission

Allogeneic sibling bone marrow transplantation (BMT) is the recommended treatment for relapsed childhood acute lymphoblastic leukaemia (ALL), but appropriate donors are only available in 30% of cases. Unfortunately, BMT from unrelated donors (UD) has been associated with high rates of severe graft-versus-host disease (GvHD) and transplant-related mortality (TRM). In an attempt to improve outcome in UD-BMT we have assessed the impact of T-cell depletion using CAMPATH-1 (anti-CD52) monoclonal antibodies in 50 consecutively referred patients with relapsed ALL in second remission. All were previously treated according to MRC protocols UKALL X and XI, and then given chemotherapy on MRC R1 from relapse until UD-BMT. 19 patients had relapsed on and 31 off therapy.
Patients and donors were fully matched at HLA-A, -B, -DR and -DQ loci in 29 cases and mismatched in 21 (four mismatched for more than one antigen). Pre-transplant conditioning comprised CAMPATH-1G, cyclophosphamide and total body irradiation. Bone marrow was T-cell depleted in vitro using CAMPATH-1 antibodies. Additional GvHD prophylaxis consisted of cyclosporin A (42 cases), cyclosporin plus methotrexate (four) or none (four). 47 patients engrafted. The incidence of acute GvHD was very low: two patients with grade II disease in the matched group, four with grade II–IV in the mismatched group. Only four patients have chronic GvHD. The actuarial event-free survival (EFS) at 2 years is 53%, with no significant difference between the matched and mismatched group. Further leukaemic relapse was the most important cause of failure.
These results are similar to the most favourable published reports for HLA-matched sibling BMT in relapsed ALL.     

Autologous bone marrow transplantation for childhood acute lymphoblastic leukaemia in second remission - long-term follow-up

From 1984 to 1996, 31 consecutive children without sibling donors, aged 5-19 years (median 8) with acute lymphoblastic leukaemia (ALL) in second complete remission (CR), received unpurged autologous bone marrow transplantation (ABMT) after melphalan and single fraction total body irradiation (TBI). ABMT was performed using fresh unmanipulated marrow harvested after standard reinduction and consolidation therapy 2-11 months (median 5) after relapse. With a median survival of 2.9 years the probability of survival for all patients in continuing second CR was 45.1% (95% CI, 24%-62%) after 5 years. Regimen-related and non-leukaemia mortality was 7% (95% CI, 2%-26%). The longest time to second relapse from ABMT was 3.1 years. Pituitary and gonadal dysfunction requiring hormonal replacement therapy occurred in the majority of long-term survivors. Twelve patients developed cataracts. ABMT with melphalan/single fraction TBI has proved an effective anti-leukaemia treatment with low regimen-related mortality but significant long-term morbidity. The current approach of allogeneic BMT from an unrelated donor when no sibling donor is available, following conditioning with cyclophosphamide/ fractionated TBI has resulted in a reduced relapse rate and improved short-term overall survival in the treatment of relapsed childhood ALL. However, long-term results are awaited.